Method for ameliorating muscle weakness/wasting in a patient infected with human immunodeficiency virus-type 1

ABSTRACT

A method for attenuating the HIV-associated myopathy and muscle wasting associated with infection by human immunodeficiency virus-Type 1. Administration of oxandrolone in a daily dosage of about 2.5 to about 20 milligrams is described.

This application a 371 of PCT US 93/10063 Oct. 20, 1993.

TECHNICAL FIELD

The invention relates to the use of oxandrolone to attenuate myopathyand muscle weakness/wasting associated with infection by human immunedeficiency virus-Type 1.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) associated myopathy and/or muscleweakness/wasting is a relatively common clinical manifestation ofacquired immunodeficiency syndrome (AIDS). This is one of a number ofneuromuscular disorders associated with the disease. There is someevidence to indicate that direct HIV infection of muscle may be at leastpartly responsible, occasionally resulting in a polymyositis-likedisorder. In addition, zidovudine (AZT), an antiviral agent that is usedwidely in the clinical management of AIDS, has been associated with atoxic myopathy, presumably related to an inhibition of mitochondrialmetabolism. In any event, the loss of muscle mass commonly observed inAIDS victims negatively impacts muscle function, however caused.

Individuals with HIV-associated myopathy or muscle weakness or wastingtypically experience significant weight loss, generalized or proximalmuscle weakness, tenderness, and muscle atrophy. Laboratory tests ofsamples from such individuals often reveal elevated levels of enzymesassociated with muscle degeneration and necrosis, such as creatinekinase, aldolase, and aspartate amino transferase. Electromyographictest results for individuals with HIV-associated myopathy are typicallyconsistent with myopathic changes. Histopathologic tests may revealmuscle fiber necrosis associated with lymphocytic inflammatoryinfiltrates. In AZT myotoxicity, ragged red fibers are often observed.

Clinical management of HIV-associated myopathy and muscleweakness/muscle wasting varies. In individuals with AZT myopathy,withdrawal of this anti-retroviral agent may be associated withtemporary improvement in strength and muscle bulk. Corticosteroidtherapy, such as the administration of prednisone, has been occasionallysuccessful when inflammatory infiltrates have been detected in muscle.However, a potential drawback to this approach is that corticosteroids,because of their immunosuppressant activity, may be harmful toindividuals with AIDS who are already dangerously immunosuppressed as aconsequence of the HIV infection.

Furthermore, corticosteroid use itself is associated with myopathies andan increased susceptibility to infections. Plasmapheresis has also beenused with some success, although at least one patient has experienced,despite an increase in muscle strength, substantial weakness over aperiod of several weeks.

SUMMARY OF THE INVENTION

The present invention provides a method which employs oxandrolone (ananabolic steroid with weak androgenic activity) as an alternativeapproach to the clinical management of HIV-associated myopathy/muscleweakness/muscle wasting. Loss in muscle mass (wasting) is attenuated,and body weight can be more readily maintained in this manner. Such anapproach has been applied successfully to improve strength, reverseweight loss, and provide an improved sense of well-being.

Importantly, no evidence of liver injury or other untoward side effectshave been observed.

Oxandrolone preferably is administered orally; however, other routes ofadministration can be utilized as well.

The present method of ameliorating muscle weakness or muscle wasting ina patient infected with HIV comprises administering to the patient dailya sufficient amount of oxandrolone to attenuate the patient's rate ofmuscle mass loss. To this end, oxandrolone may be administered, orallyor otherwise, in a daily dose in the range of about 2.5 to about 20milligrams. However, the response of individual patients may vary and insome instances a daily dose greater than 20 mg may be required toachieve the desired response. The daily dose may be divided into unitdoses of about 1 to about 5 milligrams each, administered to the patientthree times per day at about eight-hour intervals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Oxandrolone (17-hydroxy-17-methyl-2-oxaandrostan-3-one) is a knowncompound that is commercially available. The preparation of oxandroloneis described, inter alia, in U.S. Pat. No. 3,128,283 to Pappo, whichdescription is incorporated herein by reference.

Pharmacologically, oxandrolone is a synthetic anabolic steroid similarin structure to testosterone, but having a different, lesserandrogenic/anabolic activity ratio. In addition, oxandrolone is uniqueamong all other testosterone analogues in that it contains an oxygenatom instead of a methylene group at the 2-position of the phenanthrenenucleus. In addition, oxandrolone lacks a 4-ene function in its A-ring.The anabolic potency of oxandrolone, estimated as approximately 3 to 13times that of testosterone, is believed to result form this uniquestructure.

Oxandrolone disposition and metabolism in man has been studied followingoral administration of a 10 milligram dose. The study indicated thatoxandrolone was rapidly and completely absorbed, yielding a mean peakplasma concentration of 417 micrograms of Oxandrolone per milliliter at66 minutes. The plasma concentration of oxandrolone declined in abiphasic manner with a distribution half-life of approximately 30minutes and an elimination half-life of 9.4 hours. Protein binding ofoxandrolone was observed to be extensive.

In distinct contrast to other anabolic androgenic steroids such asmethyltestosterone, fluoxymesterone, and micronized testosterone,oxandrolone taken orally is excreted mainly unchanged and unconjugatedin urine. Urinary excretion of approximately 35 percent of an oraloxandrolone dose has been observed within 72 hours after ingestion.After 96 hours, approximately 65 percent of the administered oxandrolonedose was excreted in urine. Fecal excretion accounts for less than about3 percent over the same time period.

Oxandrolone compositions, upon administration in accordance with thisinvention, ameliorate myopathy and muscle weakness in patients sufferingfrom infections by human immunodeficiency virus-Type 1. Anabolicsteroids, as a class, are known to stimulate appetite. Improvednutrition is important to individuals with AIDS who have experiencedloss of lean body mass. Further, as a consequence of direct interactionwith androgen and/or glucocorticoid receptors in muscle, anabolicsteroids promote muscle anabolism through both anabolic pathways andanticatabolic pathways.

Anabolic steroids, such as oxandrolone, also increase protein synthesis.For example, oxandrolone increased muscle protein synthesis in a studyof acute uremic rats. Similarly, administration of oxandrolone precededclinical improvement in appetite, cell mass, human growth, and weightfor height in boys with chronic renal failure. These observations areconsistent with anabolic activity. Oxandrolone may also stimulate thesecretion of growth hormone and insulin-like growth factors.

In addition to producing beneficial direct anabolic action, oxandroloneis also believed to act as a delayed immunostimulant. In contrast, otherappetite stimulants, such as dronabinol, that are currently underevaluation as appetite stimulants for AIDS patients can act asimmunosuppressants in animals.

For purposes of administration in accordance with this invention, theactive ingredient oxandrolone is combined with solid or liquidpharmaceutical carriers and formulated in unit dosage form usingpharmacologically acceptable excipients, or dissolved or suspended inphysiologically acceptable solvents or liquid vehicles for oral,percutaneous, or topical administration.

The overall daily dose of oxandrolone to provide a therapeuticallyeffective amount in accordance with the method of this invention can beas low as about 2.5 milligrams and as high as about 20 milligrams,depending upon the pationt's response and the mode of administration.

The amount of the active ingredient within the aforementioned rangesthat is to be administered depends upon the age, weight and condition ofthe patient, as well as on factors such as the frequency and route ofadministration. In formulating oxandrolone, it is recognized that theremay be differences between the immediate and the long term response. Toaccount for these changes, the specific dosage given to a particularpatient is based also on the individual patient's response. Preferably,oxandrolone is orally administered to the patient daily for a timeperiod in the range of about 2 weeks to about 6 months.

Attenuation of the rate of muscle mass loss in a patient can beascertained by comparing the patient's rate of weight loss beforeoxandrolone therapy with that after the administration of oxandrolonehas been commenced. Alternatively, or in addition, the patient's urinarynitrogen level can be monitored, a well-known expedient. A decrease inthe patient's urinary nitrogen level is indicative of a decrease inmuscle mass loss.

Similarly, the maintenance of a relatively stable patient's total bodypotassium level, as well as an increase in the patient's total bodypotassium level, upon oxandrolone administration indicates that atherapeutically effective amount of oxandrolone is being administered. Apatient's total body potassium level can be monitored, for example, asdescribed in Kotler et al., The American Journal of Clinical Nutrition,42:1255-1265 (December 1985) and Pierson, Jr., et al., Am. J. Physiol.,246 (Renal Fluid Electrolyte Physiol. 15) :F234-F239 (1984).

The route of administration can be oral, percutaneous, transdermal,sublingual, buccal, intravenous, intramuscular, or the like. Of these,oral administration is preferred. The patient's daily dose of the activeingredient preferably is in the range of about 7.5 milligrams, but mayexceed 20 milligrams based on clinical response. This daily dose can begiven in tablet form as a single dose, or as plural divided doses,preferably 2 to 3 divided doses. The requisite daily dose can also besupplied continuously, for example, by a transdermal patch worn by thepatient or intravenously. If the oxandrolone is administered orally,dosages in the range of about 2 to about 5 milligrams three to fourtimes daily typically may be prescribed.

Oxandrolone tablets are manufactured using standard solid dose formtechnology in accordance with United States Pharmacopeia (USP)specifications (see, for example, The United States Pharmacopeia, 22ndRevision, pp. 981-982). Specifically, a typical 150-milligram tabletcontains the following:

    ______________________________________                                        Oxandrolone, USP          2.5 mg                                              Corn Starch, NF           30.0 mg                                             Lactose NF (hydrous)     113.0 mg                                             Hydroxypropyl Methylcellulose, USP                                                                      3.0 mg                                              Magnesium Stearate        1.5 mg                                                                       150.0 mg                                             ______________________________________                                    

The terms "unit dosage form" and "unit dose" as used in the presentspecification and claims refer to a physically discrete unit or unitssuitable as unitary doses for patients, each unit containing apredetermined quantity of the active ingredient calculated to producethe desired therapeutic effect in association with the pharmacologicallyacceptable carrier. The specifications for the unit dosage forms of thisinvention are dictated in part and are also dependent upon (a) theunique characteristics of the active ingredient and (b) the particulartherapeutic effect to be achieved, as well as upon limitations inherentin the art of compounding such active ingredient for the therapeutic usedisclosed in detail in this specification. Examples of suitable unitdosage forms in accordance with this invention are tablets, pills,powder packets, wafers, cachets, segregated multiples of any of theforegoing, transdermal patches, aliquots of injectables, and the likeforms.

The primary response variables are patient's total body potassium, bodyweight, muscle mass, muscle strength, improvement in or increasedappetite, and general sense of well-being. In addition, improvement inimmune status (or at a minimum, no worsening of immune function) inresponse to oxandrolone is significant as well.

An important question regarding the use of any drug in combination withanti-retroviral therapy is whether drug interactions may occur thatwould diminish AZT efficacy or increase the frequency of severity ofAZT-related adverse reactions. TABLE 1 compares various publishedpharmacological parameters for oxandrolone and AZT and illustratesimportant differences between the two drugs.

                  TABLE 1                                                         ______________________________________                                        Comparison of Selected Oxandrolone                                            and AZT Pharmacology Parameters                                               Parameter Oxandrolone  AZT                                                    ______________________________________                                        Oral      100%         65%                                                    Bioavailability                                                               Tmax      1.1 hr       0.7 hr                                                 Biological T1/2                                                                         9.4 hr       1.1 hr                                                 Vd        578 ml/kg    >1400 ml/kg                                            Protein Binding                                                                         >95%         25-35%                                                 Plasma Clearance                                                                        43 ml/kg/hr  >1300 ml/kg/hr                                         Metabolism                                                                              Little       Extensive                                              Glucuronidation                                                                         Little       Substantial                                            Urinary Excretion                                                                       Extensive; primarily                                                                       Extensive; parent and                                            parent compound                                                                            glucuronide conjugated                                 Target Organ                                                                            Liver (anabolic                                                                            Hematopoietic system                                   Toxicity  steroids as a class)                                                                       (e.g., anemia, granulocytopenia)                       Known Drug                                                                              Anticoagulants; oral                                                                       Drugs that may: (a) inhibit                            Interactions                                                                            hypoglycemic glucuronidation (e.g., aspirin,                                  agents; adrenal                                                                            acetaminophen) or urinary                                        steroid when excretion (e.g., probenecid);                                    edema present                                                                              (b) adversely affect blood cell                                               number and function; and (c)                                                  nephrotoxic or cytotoxic                               ______________________________________                                    

Because oxandrolone is primarily protein bound, whereas AZT is primarilynon-protein bound, oxandrolone will not compete appreciably with AZT forbinding sites in plasma. Consequently, administration of oxandrolone topatients on AZT therapy is unlikely to alter the level of free AZT inthe blood. Likewise, the administration of AZT is unlikely to alter thelevel of free oxandrolone in the blood. An oxandrolone-AZT druginteraction involving binding site displacement is, therefore, extremelyunlikely.

AZT is rapidly metabolized and excreted in the urine--a significantquantity is excreted in the form of glucuronide conjugates. In sharpcontrast, oxandrolone, perhaps due to presence of a lactone group andthe absence of a 4-ene function in the A-ring, undergoes little hepaticmetabolism and is excreted primarily unchanged and unconjugated inurine. Thus, in contradistinction to other drugs that may competitivelyinhibit glucuronidation and thereby potentially slow the rate of AZTmetabolism, such as aspirin, acetaminophen, or indomethacin, the presentactive agent, oxandrolone, is not believed to affect AZT metabolism.

Furthermore, oxandrolone is neither nephrotoxic nor cytotoxic.Accordingly, oxandrolone is not expected to interfere with the renalexcretion of AZT or its metabolites. To the contrary, oxandrolone hasbeen safely and effectively used in patients with chronic renal diseaseto stimulate growth and increase lean body mass. In well-controlledstudies of oxandrolone for the clinical management of critically illpatients with acute alcoholic hepatitis, oxandrolone administered atdaily doses of up to 80 mg/day for four weeks and 40 mg/day for eightweeks did not result in any drug-related nephrotoxicity.

While it is known that anabolic androgenic steroids have been associatedwith potentially life-threatening forms of liver disease, includingpeliosis hepatis, cholestatic jaundice, and hepatocellular neoplasms,specific reports in the medical literature regarding liver disease inoxandrolone-treated patients, at the dosages proposed for use in theclinical management of HIV associated muscle weakness/wasting (i.e.,about 2.5 to about 20 mg/day) are rare.

Oxandrolone and AZT have different mechanisms of action. They alsofunction in different sites of cellular action at the receptor level.Oxandrolone functions via interaction with androgen and glucocorticoidreceptors, whereas AZT, once phosphorylated, acts to inhibit HIV reversetranscription. Thus, competitive inhibition of AZT by oxandrolone at thecellular level also is considered unlikely.

Neither has oxandrolone been associated with anemia or granulocytopenia,two frequently occurring and potentially serious side effects associatedwith AZT therapy. To the contrary, anabolic androgenic steroids havebeen used clinically to stimulate ethyropoiesis in hypoanemias, aplasticanemias, hemolytic anemias, renal anemias, anemias due to cytotoxictherapy, and various leukemias. It has been reported recently thatandrogens augment beneficial effects of erythropoietin in the treatmentof anemia resulting from end-stage renal disease.

Data derived from animal models and human clinical studies indicate thatanabolic steroids are unlikely to suppress immune function in patientsinfected with HIV. For example, anabolic steroids can stimulategranulopoiesis in mice, as evidenced by stimulation of granulocyticcolony-forming cells derived from spleen and bone marrow. Similarly, ananabolic steroid known as nandrolone decanonate enhanced macrophageactivity and cell-mediated immunity in patients with uterine cervicalcancer when administered parentally. In related studies, anabolicsteroids increased peripheral lymphocyte and monocyte counts,Immunoglobin G (IgG) levels, and PHA-blastoid transfromation ofperipheral lymphocytes. In those studies, β₂ -microglobulin levelssimultaneously decreased.

IgG is one of a class of antibodies secreted by B cells (i.e.,B-lymphocytes) in response to an antigenic challenge (e.g., foreignprotein like that from bacteria). In the case of HIV infection, humoralimmune function (i.e., B-cell mediated) is significantly impaired.Accordingly, when HIV-infected individuals are challenged with aspecific antigen, the typical response of B-cell proliferation,differentiation and secretion of antibodies (e.g., IgG) is diminished orabsent. This decline in humoral immune function coupled with defects incellular immune (i.e., T-cell) function contributes to the overallfailure of the immune system to respond in an appropriate manner tochallenge. B-cells in AIDS victims are, by mechanisms unknown,hyperstimulated to secrete large amounts of immunoglobulins that makethe humoral system refractory to new antigens. The result is that thepatient's system no longer recognizes new antigens and does not respond.

In animal studies in which anabolic steroids have been reported toincrease IgG and PHA-blastoid activity, these changes occurred as aresult of immune system stimulation, and are positive responses.β-microglobin is a cell surface protein that is found on all nucleatedcalls and it is released into the serum during cell turnover. Generally,β-microglobulin is considered a marker of infectious, inflammatory,malignant and autoimmune disease activity. In several AIDS studies,β-microglobulin levels correlated with disease progression and T4(T-helper) cell counts. In the case of therapy with oxandrolone, forexample, a decrease in β-microglobulin levels is desirable. Thus, animaldata showing reduced plasma levels of β-microglobulin in response toanabolic steroids is evidence of a positive effect and suggestive ofsimilar activity in man.

Accordingly, there are no reasons to believe that the administration ofan anabolic steroid in general and oxandrolone in particular would haveadverse effects on the immune system. Generally, the target organ oftoxicity for these drugs is the liver--probably because this is wheremost are metabolized. Oxandrolone, however, has a remarkably good safetyprofile in man as a likely consequence of its resistance to hepaticmetabolism; an oral dose is excreted primarily in urine as the parentcompound, as stated hereinabove.

Data from clinical trials in patients with severe alcoholic liverdisease provide further evidence that oxandrolone is not likely tosuppress immune function in patients with HIV infection. Ethanol abuseis associated with loss of lymphocyte functions, particularly T-celldependent immune responses. Previous researchers have observed thatoxandrolone significantly improved lymphocyte number in patients withsevere alcoholic hepatitis. Because the loss of lymphocytic function byalcoholic liver disease parallels, to a significant degree, the loss ofT-cell function due to HIV infection, it is reasonable to hypothesizethat oxandrolone will increase the T-Cell function of HIV-infectedpatients.

Therefore, these data from laboratory animals and human studies indicatethat suppression of the immune system by anabolic steroids, such asoxandrolone, is unlikely. Nonetheless, subjects undergoing oxandrolonetherapy, as a precaution, should be monitored for changes in lymphocytenumber, particularly CD4+ and CD8+, as is routinely done for patientswho undergo steroid therapy.

In summary, based on the differences between AZT and oxandrolone withrespect to pharmacokinetics, metabolism, reported drug interactions,mechanisms of action, and reported toxicities, oxandrolone and AZT canbe safely used in combination for subjects infected with the Type-1 HIVvirus and suffering from HIV-associated myopathy. The use of oxandrolonein patients on AZT therapy is, on the basis of known drug interactions,also consistent with current FDA-approved labeling for AZT andoxandrolone.

The following example demonstrates the effectiveness of oxandrolone inattenuating the effects of HIV-associated muscle weakness or musclewasting in an AIDS patient.

EXAMPLE

A patient, a thirty-two year old homosexual man, known to beHIV-seropositive since February 1989, noted difficulty opening drawersand bottles in May 1989. The patient weakened progressively and, duringa physical examination in September 1989, demonstrated by confrontationtesting the weakness of neck flexion and proximal limbs. However, hismuscle stretch reflexes remained normal. Laboratory tests showed thepatient's creatine kinase level to be 286 International Units per liter,much higher than the normally observed range for creatine kinase ofabout 40-200 Units per liter.

Zidovudine (azidothymidine or AZT) was initiated at 500 milligramsdaily, but the patient's strength continued to decline through February1990. He complained of an inability to ascend a flight of stairs. Thepatient exhibited greater weakness and atrophy of neck flexors andextremity muscles during another physical examination performed at thistime. An electromyogram revealed a decrease of amplitude and duration ofthe patient's motor unit potentials and increased recruitment inselected muscles of his right upper extremity. The patient's creatinekinase tested at 456 Units per liter. A muscle biopsy revealed numerousmyofibers, abundant ragged red fibers, and numerous eosinophilicinclusions. Round cell inflammatory infiltrates were also noted. Inlight of these developments, the zidovudine treatment was terminated.

Substantial improvement initially followed the discontinuation ofzidovudine. However, because of a subsequent continued and progressiveweakness rendering it difficult for the patient to ascend or descend aflight of stairs, a prednisone therapy (60 mg daily) was initiated. Nosignificant improvement accompanied the use of prednisone.

Thereafter, a trial period of oral oxandrolone administration (2.5milligrams, three times daily, in tablet form) was initiated. Within twoweeks of the initiation of the oxandrolone therapy, the patient noted animproved sense of well being, became stronger, and gained weight. Withinone month, he was able to ascend and descend stairs without problems.Confrontation testing revealed nearly normal strength. The patient'sweight increased from 115 pounds to 130 pounds. The patient's muscleatrophy was alleviated as well. Liver functions were closely monitoredfor signs of elevation, but undesirable side effects were not detected.

After several months of the aforementioned therapy with oxandrolone, thepatient was no longer able to obtain oxandrolone for use as amedication. Weakness and weight loss ensued. Trials of other anabolicpreparations, specifically stanazol and oxymethalone, did not return thepatient to his previous levels of function and strength.

The EXAMPLE demonstrates that oxandrolone can be a beneficialalternative for clinical management of HIV-associated myopathy andmuscle weakness and wasting.

It is intended that the foregoing description is by way of illustrationonly and is not to be construed as limiting the invention in any wayexcept in the spirit and scope of the appended claims.

What is claimed is:
 1. A method for ameliorating HIV-associated myopathyand muscle weakness in an AIDS patient which comprises orallyadministering oxandrolone to the AIDS patient in a daily dosage ofbetween about 2.5 to about 7.5 milligrams.
 2. The method in accordancewith claim 1 wherein the daily dosage of the oxandrolone is about 7.5milligrams.
 3. The method in accordance with claim 1 wherein theoxandrolone is administered to said patient as a unit dose of about 1 toabout 2.5 milligrams three times per day at about eight-hour intervals.4. The method in accordance with claim 1 wherein the oxandrolone isadministered in the form of a tablet.
 5. The method in accordance withclaim 1 wherein administration is continued over a period of about 2weeks.
 6. The method in accordance with claim 1 wherein administrationis continued over a period of about 2 weeks.
 7. The method in accordancewith claim 3 wherein administration is continued over a period of about2 weeks.
 8. A method for ameliorating HIV-associated myopathy and musclewasting in an AIDS patient which comprises orally administering atherapeutically effective amount of oxandrolone to the AIDS patientdaily for a time period of about 2 weeks.